Romidepsin, initially isolated from Chromobacterium violaceum, is a bicyclic peptide inhibitor of Class I histone deacetylases. Accumulation of acetylated histones induces cell cycle arrest and apoptosis in some cancer cell lines, although the exact mechanism of its anticancer effect is not clear. Romidepsin is a prodrug and requires reduction of disulfide bonds for activation.
Exhibited linear pharmacokinetics over the recommended dosing range. No accumulation was observed after repeat dosing.
|Peak plasma levels||3 hours (median)|
Rapid distribution into many tissue and organ systems. Accumulates into human hepatocytes via an unknown uptake mechanism.
|PPB||92-94%, mainly to alpha-1 acid glycoprotein|
|Cross blood brain barrier?||Very low|
|Main enzymes involved||mainly CYP 3A4, minor with CYP3A5, 1A1, 2B6, 2C19. Also a substrate of Pgp and MRP1.|
|Inactive metabolites||approximately 30, each < 5% of total dose|
Multiphasic elimination; mainly eliminated through bile with excretion into feces. Age, gender and race did not appear to affect the pharmacokinetics of romidepsin.
|Urine||<20%, with <5% parent drug|
(pending the result of studies to verify the drug’s clinical benefit. Patients should be advised of the nature of the marketing authorization granted.)
For the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) who are not eligible for transplant and have received at least one prior systemic therapy.
Approval in peripheral T-cell lymphoma was based on response rates; improvement in overall or progression-free survival has not been demonstrated.
Extravasation Potential: Minimal
The following adverse effects were reported from the pivotal single arm clinical trial.
|ORGAN SITE||SIDE EFFECT* (%)||ONSET**|
|Cardiovascular||Hypotension (8%)||I E|
|QT interval prolonged (rare)||E|
|Venous thromboembolism (4%)||E|
|Gastrointestinal||Abdominal pain (14%)||E|
|Anorexia, weight loss (28%)||E|
|Nausea, vomiting (59%)||I|
|Fatigue (55%) (severe 8%)||E|
|Hematological||Myelosuppression ± infection, bleeding (29%) (grade 3 or 4, including opportunistic infections/ viral reactivation)||E|
|Hepatobiliary||↑ LFTs (29%) (severe 2%)||E|
|Metabolic / Endocrine||Abnormal electrolyte(s) (11%) (especially hypomagnesemia, hypokalemia)||E|
|Tumor lysis syndrome (2%)||I|
|Musculoskeletal||Musculoskeletal pain (9%)||E|
|Nervous System||Anxiety (7%)||E|
|Respiratory||Cough, dyspnea (18%)||E|
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
Dose-limiting side effects are underlined.
** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)
The most common side effects for romidepsin include nausea/vomiting , fatigue, myelosuppression ± infection/bleeding, diarrhea, constipation, ↑ LFTs, anorexia/weight loss, dysgeusia, cough/dyspnea and headache.
Gastrointestinal adverse effects such as nausea, vomiting, constipation and diarrhea were generally mild to moderate.
Serious or fatal infections have been observed during treatment and within 30 days after treatment. Patients with a history of bone marrow involvement or prior treatment with monoclonal antibodies directed against lymphocyte antigens may have high risk of infections. Viral reactivation (hepatitis B, CMV, EBV) has been described; consider prophylaxis and monitoring patient.
Refer to protocol by which patient is being treated. Plasma potassium and magnesium levels should be within normal range before each romidepsin administration; do not treat if QTc > 480 ms. Patients at risk of tumour lysis syndrome should have appropriate prophylaxis and be monitored closely.
Dose levels: Do not re-escalate reduced doses.
|Dose level||Dose (On days 1, 8, 15)|
|Starting dose||14 mg/m2|
|First reduction||10 mg/m2|
Q 28 day cycle:
Intravenous: 14 mg/m² Days 1, 8, 15
Worst Counts (x109/L) / Toxicity
Grade 2 or 3 non-hematological/ organ
Hold*, restart at same dose level
If grade 3 recurs, hold* then ↓ 1 dose level.
If grade 3 recurs after dose reduction, discontinue.
|Grade 4 non-hematological/ organ||
Hold*, restart by ↓ 1 dose level
If grade 3 or 4 recurs after dose reduction, discontinue.
Grade 3 or 4 ANC or platelets
Hold*, restart at same dose level
|Grade 4 febrile neutropenia or thrombocytopenia requiring platelet transfusion||Hold*, restart by ↓ 1 dose level|
Not formally studied. Population pharmacokinetic analysis suggested the following:
|≤ ULN||and||> ULN||No change (no significant pharmacokinetic differences)|
|1 to 1.5 x ULN||and||any||No change (no significant pharmacokinetic differences)|
|>1.5 to 3||and||any||Caution (no data)|
|> 3 x ULN||and||any||Caution (no data)|
Not formally studied. Population pharmacokinetic analysis suggested that renal impairment was not expected to affect drug exposure significantly:
|Mild (> 50-80)||No change|
|Moderate (30-50)||No change|
|Severe (< 30)||No change|
|ESRD||Caution (no data)|
No overall safety and efficacy differences were observed between elderly and younger patients; however, elderly patients may require dose modifications due to increased risk of toxicity.
Safety and efficacy have not been established in patients < 18 years of age.
- Reconstitute romidepsin using the supplied diluent. Refer to the product monograph for instructions.
- Add the required dose into 500 mL 0.9% Sodium Chloride (NS).
- Infuse IV over 4 hours.
- Missed doses should be administered as soon as possible, unless it is within 5 days of the next scheduled dose
- Diluted solution is compatible with PVC, ethylene vinyl acetate (EVA) polyethylene (PE) infusion bags as well as glass bottles
- Store unopened vial and diluent together at room temperature (15 to 30oC)
- The manufacturer recommends that the reconstituted drug is stable for at least 8 hours when stored at room temperature. After dilution with 0.9% sodium chloride solution (NS), it is stable up to 24 hours at room temperature
- Patients who have hypersensitivity to this drug or any of its components
- Baseline QT prolongation > 480 ms
- Patients with congenital long QT syndrome
- Abnormal plasma magnesium or potassium levels
- Patients with a significant cardiac history were excluded from clinical trials; exercise extreme caution in these patients
- Use with caution in patients who are at risk of experiencing torsade de points or QT prolongation, including female patients, age ≥ 65 years, congenital long QT syndrome, cardiac disease, history of arrhythmias, electrolyte disturbances, bradycardia, acute neurological events, diabetes, on concomitant antiarrhythmics or drugs that prolong QT, or autonomic neuropathy
- Use with caution in patients with bulky disease due to the risk of tumour lysis syndrome
- Use with caution in patients with compromised bone marrow (disease, or heavily pretreated) due to the risk of infection
Other Drug Properties:
Romidepsin is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 8 weeks after the last dose. Estrogen-containing contraceptives should not be used (refer to interactions). Male patients, including vasectomized males, should use condoms with spermicide.
It is not known whether romidepsin is excreted into human milk.
These effects may be irreversible.
Romidepsin does not significantly inhibit or induce CYP450 substrates, but is susceptible to drug interactions from CYP3A4 inhibitors/inducers.
|CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit)||↑ romidepsin concentration and/or toxicity||↓ metabolism of romidepsin||Avoid use with strong inhibitors. Caution with moderate inhibitors; monitor for toxicity|
|CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc)||↓ romidepsin concentration/efficacy (theoretical), ↑ romidepsin exposure observed with rifampin||↑ metabolism of romidepsin; rifampin may inhibit hepatic uptake that limits romidepsin access to induced CYP3A4||Avoid strong CYP3A4 inducers|
|Coumarin derivatives||↑ PT and INR observed||Unknown||Caution; monitor PT and INR closely|
|Estrogen containing contraceptives||↓ effectiveness of estrogen-containing contraceptives||Competition with binding to the estrogen receptors||Caution; use alternate non-estrogen contraception (e.g. condoms, IUD); monitor for estrogen deficiency in patients on hormone replacement therapy|
|P-glycoprotein inhibitors (i.e. quinidine, verapamil, cyclosporine)||↑ Romidepsin concentration and/or toxicity||↓ Romidepsin elimination||Caution|
|Drugs that may prolong QT (i.e. amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc)||↑ QT prolongation effect||Additive||Caution; monitor patient closely|
|Drugs that disrupt electrolyte levels (i.e. loop/thiazide diuretics, laxatives, amphotericin B, high dose corticosteroids)||↑ risk of QT prolongation||Electrolyte disturbance||Avoid if possible|
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
|Monitor Type||Monitor Frequency|
Electrolytes, including potassium and magnesium
|baseline, before each cycle and as clinically indicated|
|INR and PT for patients taking warfarin or its derivatives||baseline and regular|
|CBC||baseline and before each treatment (at minimum)|
ECG; baseline; baseline and periodic for patients at risk of QT prolongation
|baseline and as clinically indicated|
Clinical toxicity assessment for infection, bleeding, thromboembolism, fatigue, GI effects, hypersensitivity, tumour lysis syndrome
|at each visit|
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
New Drug Funding Program (
- Romidepsin - Relapsed or Refractory Peripheral T-Cell Lymphoma
Coiffier B, Pro B, Prince HM, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol 2012 Feb 20;30(6):631-6.
Product Monograph: Istodax® (romidepsin). Celgene Inc., December 13, 2016.
Yang LPH. Romidepsin: in the treatment of T-cell lymphoma. Drugs 2011;71(11):1469-80.
November 2017 added reference to product monograph in administration section
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